Hepatic Overexpression of Heme Oxygenase-1 Improves Liver Allograft Survival by Expanding T Regulatory Cells

Sun, Liang; Shi, Tiefeng; Qiao, Haiquan; Jiang, Xian; Jiang, Hongchi; Krissansen, Geoffrey W.; Sun, Xueying

doi:10.1016/j.jss.2010.11.917

« Previous Next »Journal of Surgical Research
Volume 166, Issue 2 , Pages e187-e194, April 2011

Hepatic Overexpression of Heme Oxygenase-1 Improves Liver Allograft Survival by Expanding T Regulatory Cells

Liang Sun, M.D.
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
Tiefeng Shi, M.D.
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
Haiquan Qiao, M.D., Ph.D.
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
- To whom correspondence and reprint requests should be addressed at Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Xian Jiang, M.D., Ph.D.
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
Hongchi Jiang, M.D., Ph.D.
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
Geoffrey W. Krissansen, Ph.D.
- Department of Molecular Medicine & Pathology, the University of Auckland, Auckland, New Zealand
Xueying Sun, M.D., Ph.D.
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Molecular Medicine & Pathology, the University of Auckland, Auckland, New Zealand
- Department of Molecular Medicine and Pathology, the University of Auckland, Auckland 1005, New Zealand.

Received 24 August 2010 published online 27 December 2010.

Background

Heme oxygenase (HO)-1 protects transplanted organs from ischemia reperfusion injury and immune rejection. This study sought to investigate whether persistent overexpression of HO-1 in donor livers could improve the survival by expanding T regulatory cells in a rat model of orthotopic liver transplantation.

Methods

Livers of Dark Agouti rats were intraportally perfused with an AAV expression vector encoding rat HO-1 (AAV-HO-1), and then transplanted into Lewis rats. The survival, HO-1 activity, Banff rejection activity index, serum levels of IL-2 and TNF-α, infiltration of CD4⁺, CD8⁺, and T_reg (CD4⁺CD25⁺Foxp3⁺) cells into donor livers, and expression of Foxp3, TGF-β, and IL-10 were examined. A mixed lymphocyte reaction (MLR) was performed.

Results

Intraportal delivery of AAV-HO-1 resulted in persistent expression of HO-1 and increased activity of HO-1 in transplanted livers, leading to prolonged survival of recipients. Overexpression of HO-1 reduced the Banff rejection activity index, and production of IL-2 and TNF-α, inhibited infiltration of CD4⁺ and CD8⁺ cells, and increased infiltration of T_reg cells, into donor livers. The spleens of recipients expressed higher levels of Foxp3, TGF-β, and IL-10 than those of control rats, and the transplanted livers expressed higher levels of Foxp3 and TGF-β. Splenocytes from the tolerant recipients had higher percentages of T_reg cells, and responded poorly to the allogeneic donor splenocytes.

Conclusions

Persistent expression of HO-1 in donor livers by intraportal delivery of AAV-HO-1 improves the survival by expanding T_reg cells. HO-1-based therapies, as described herein, promise new strategies to prevent the rejection of liver transplants.

Key Words: heme oxygenase-1, liver transplantation, immune rejection, T regulatory cells, adeno-associated virus